Osteoarthritis or degenerative chronic arthropathy is a chronic joint disease characterized by structural deterioration of joint cartilage. The symptoms of this pathological condition can vary depending on the joint concerned, but are generally characterized by persistent pain associated with a functional impairment, i.e., a limitation of the mobility of the joint concerned.
Joint cartilage is a connective tissue composed of chondrocytes and an extracellular matrix essentially formed from water, proteoglycans and collagen. Chondrocytes have a fundamental role in the homeostasis of the extracellular matrix in which they ensure its synthesis and renewal. The maintaining of cartilage therefore depends on continuous complex exchanges between the chondrocytes and the matrix and is continually subjected to a critical equilibrium between the degradation mechanisms, under the influence of destructive cytokines, in particular the pro-inflammatory cytokines TNF-α and IL-1β, and the synthesis or restoring mechanisms under the effect of modulating cytokines and growth factors, in particular IGF-1, TGF-β, and certain BMPs (bone morphogenetic proteins).
The arthrotic destruction of cartilage is the result of an imbalance between the anabolic and catabolic mechanisms of the extracellular matrix. Several factors can promote rupturing of the homeostasis of the matrix, in particular mechanical factors associated, for example, with joint overload in an obese patient, trauma, repeated microtraumas or architectural defects of the joint, metabolic, genetic or hormonal factors, or aging. However, the initiation of the arthrotic process still remains very poorly understood at the current time.
The imbalance between the anabolic and catabolic mechanisms essentially results in an increase in the synthesis of metalloproteases (MMPs) (Blanc et al., 1999), a decrease in the synthesis of TIMPs (tissue inhibitors of metalloproteinases, the physiological inhibitors of MMPs) and an inhibition of matrix constituent synthesis by chondrocytes. This imbalance is accentuated by an accelerated chondrocyte apoptosis phenomenon (Hashimoto et al., 1998) and by chondrocyte activation via various mediators released by the synovial tissue (Sellam and Berenbaum, 2010). The pro-inflammatory cytokine IL-1β synthesized by chondrocytes and synoviocytes has a major role in this arthrotic destruction process. It induces not only an increase in MMP production by chondrocytes, but also a reduction of the anabolic capacities and the apoptosis of these cells (Goldring et al., 2008). Furthermore, the subchondral bone also participates in matrix-degrading phenomena, in particular by means of the secretion of proteolytic enzymes by osteoblasts (Sanchez et al., 2012).
The matrix metalloproteases (MMPs) involved in the matrix proteolysis of osteoarthritis are collagenases, stromelysins, gelatinases and membrane metalloproteases (Rannou et al., 2005). Not all of these enzymes are specific for cartilage, and they are involved in numerous physiological processes, in particular the remodeling of numerous connective tissues (Nagase et al., 1999). The interstitial collagenases (MMP-1, -8, and -13) are capable of degrading collagens I, II, III, IV and VII. The collagen thus denatured by these enzymes becomes a substrate for gelatinases. The stromelysins (MMP-3, -10, and -11) are capable of degrading proteoglycans, gelatin, fibronectin and collagen type IX, but only MMP-3 appears to be involved in the degradation of the cartilaginous matrix (Stove et al., 2001). The gelatinases (MMP-2 and -9) degrade denatured interstitial collagen and collagens IV and V. In addition, it has been demonstrated that MMP-1, -3 and -13 are also capable of degrading proteoglycans (Little et al., 2002). Other enzymes, in particular the aggrecanases ADAMTS-4 and -5, are also thought to play a role in matrix proteolysis (Fosang and Little, 2008).
In addition to metalloproteases, other catabolic mediators participate in arthrotic degeneration, in particular prostaglandin E2 (PGE2), which is involved in cartilage degradation and chondrocyte apoptosis (Hardy et al., 2002; Miwa et al., 2000).
The treatments proposed for patients suffering from osteoarthritis are symptomatic since, at the current time, there is no curative treatment for this pathological condition. The drug treatments are symptomatic treatments with an immediate action (analgesics, non-steroidal anti-inflammatories) or with a delayed action (for example, drugs comprising chondroitin sulphate (Structum, Chondrosulf), diacerein (Art 50, Zondar), unsaponifiable extracts of avocado and of soya (Piascledine) or hyaluronic acid.
Because of their key role in cartilage destruction, metalloproteases have become favoured targets in the search for new compounds capable of slowing down or stopping the progression of osteoarthritis. However, these proteins are involved in numerous physiological processes and inhibiting them may produce unforeseeable side effects. That was, for example, the case with the compound PG-116800, the musculoskeletal toxicity of which was revealed during clinical trials (Krzeski et al., 2007).
Currently, osteoarthritis is thought to affect approximately nine to ten million individuals in France, including 4.6 million with symptomatic osteoarthritis. Given the aging of the population and also the increase in the prevalence of obesity in developed countries, a very large increase in the number of arthrotic patients is expected in the coming years. This increase will be extremely expensive, not only in terms of quality of life, but also from an economic point of view for treating the patients. It therefore remains essential to rapidly develop new strategies for inhibiting or slowing down cartilage destruction in individuals suffering from osteoarthritis.